DESCRIPTION (Applicant's Abstract): A new medication for drug abuse and drug craving is proposed. Positive results have been obtained with the combination of properties in two appetite suppressants, the serotonergic drug fenfluramine (Fen) and the dopamineric drug phentermine (Phen). The Fen-Phen combination decreased oral intake of nicotine in mice, decreased i.v. self-administration of cocaine+heroin in rats, and decreased binge eating and food craving in humans. The proposal for animal research is to investigate where, how, and when Fen-Phen works, and for humans, to determine whether it is an effective medication to reduce nicotine and cocaine craving. Fen-Phen probably suppresses appetite via the hypothalamus. Most drugs of abuse act on the mesolimbic dopamine (DA) system that generates conditioned incentives and behavior reinforcement. Therefore, the logic behind Fen-Phen therapy for drug abuse is to activate hypothalamic systems for appetite suppression in a manner that imposes limits on the DA incentive/reinforcement system. This will inhibit conditioned or unconditioned stimuli for drug abuse. [The application is designed to address the following questions:] 1. Where does Fen-Phen work? At the behavioral level, the proposed plan is to compare d- and d,l-fenfluramine and phentermine, separately and together for efficacy in inhibiting drug self-administration in rats and for locomotor side effects, abuse liability, and sites of action in the hypothalamus and a DA terminal region. 2. How does Fen-Phen work? At the neural systems level, our studies suggest that Fen-Phen acts in the hypothalamus to inhibit drug abuse by releasing acetylcholine in nucleus accumbens (NAc), where acetylcholine can limit dopamine's effects. Drugs and neurotransmitters in the brain will be measured by microdialysis. 3. When does Fen-Phen work? Food deprivation and weight loss are known to augment drug abuse. It was discovered that food-restricted rats with low body weight have low DA release in the NAc. Therefore, food restricted animals may be prone to drug abuse as a means to restore DA. Fen-Phen may have special potential in drug abuse prevention or treatment in situations that benefit from appetite suppression. The above three studies will clarify the mechanism and potential of Fen-Phen therapy.